Water-swellable polymers

ABSTRACT

A water-swellable linear polyurethane polymer is formed by reacting a polyethylene oxide (e.g. PEG 4000 to 35,000), a difunctional compound (e.g. a diamine or diol such as 1,10-decanediol) with a diisocyanate. The ratio of the three components is generally in the range 0.1-1.5 to 1 to 1.1-2.5. The polyurethane is water-swellable in the range 300 to 1700% and soluble in certain organic solvents such as dichloromethane. It can be loaded with pharmaceutically active agents, particularly of high molecular weight, to produce controlled release compositions, such as pessaries etc.

The present invention relates to water-swellable linear polymers,suitable for the production of controlled release compositions forrelease of pharmaceutically active agents over a prolonged period oftime.

Certain cross-linked polyurethane polymers are known from EuropeanPatent Publication EP0016652 and EP0016654. These patent specificationsdescribe cross-linked polyurethanes formed by reacting a polyethyleneoxide of equivalent weight greater than 1500 with a polyfunctionalisocyanate and a trifunctional compound reactive therewith, such as analkane triol. The resultant cross-linked polyurethane polymers arewater-swellable to form a hydrogel but are water-insoluble and may beloaded with water-soluble pharmaceutically active agents. One particularpolyurethane polymer is the reaction product of polyethylene glycol8000, Desmodur (DMDI i.e. dicyclohexylmethane-4,4-diisocyanate) and1,2,6-hexane triol and which has been used commercially for vaginaldelivery of prostaglandins.

However, such polyurethane polymers possess a number of practicaldisadvantages. Whilst the use of a triol cross-linking agent iseffective in providing polymers of relatively reproducible swellingcharacteristics, the percent swelling is typically 200-300% (i.e. theincrease in weight of the swollen polymer divided by the weight of thedry polymer). Pharmaceutically active agents are loaded by contactingthe dry polymer with an aqueous solution of pharmaceutically activeagent, such that the solution becomes absorbed into the polymer, forminga hydrogel. The swollen polymer is then dried back to a chosen watercontent before use. A consequence is that with the conventionalcross-linked polyurethane, the degree of swelling limits the molecularweight of the pharmaceutically active agent which can be absorbed intothe hydrogel structure to below about 3000. A further disadvantage isthat only water-soluble pharmaceutically active agents may be used.Finally, since the conventional cross-linked polyurethane polymer isessentially insoluble in both water and organic solvents, processing ofthe formed polymer into other solid forms, such as films or coatings, isnot possible.

The object of the present invention is to provide a polyurethane polymerof the aforementioned type which is not cross-linked but is linear butwhich still possesses the desirable properties of reproducibleswellability found in the prior cross-linked polyurethanes.

Initial work on the production of linear polyurethane polymers provedunsatisfactory, since the polymers were not stable but continued toreact over extended time periods. Also, the swellability was notconstant or reproducible, and changed with time.

The present invention is based on the discovery that linearpolyurethanes having suitable characteristics may be obtained byreacting a polyoxyethylene glycol with a diol or other difunctionalcompound and a difunctional isocyanate.

In particular, the present invention provides a water-swellable linearpolymer obtainable by reacting together

(a) a polyethylene oxide;

(b) a difunctional compound; and

(c) a difunctional isocyanate.

Alternatively stated, the invention provides a water-swellable linearpolyurethane formed of moieties derived from (a), (b) and (c) bondedtogether.

The linear polymer produced is swellable in water to an enhanced degree,depending upon the ratio of the three components (a), (b) and (c), forexample up to 500%, up to 800% or even above 1,000%, thus allowinghigher molecular weight pharmaceutically active water-soluble agents tobe loaded into the swollen hydrogel derived from the linear polymer.Usually, the polymer is swellable to 200% to 2000%, for example 250 to1700%. Depending on the particular active agent, swellabilities in theranges 300-1000, 400-800, 1000-1500, 1100-1300 etc., may be achievedwith the polyurethanes of the invention. The linear polymer of theinvention is also soluble in certain organic solvents, such asdichloromethane, which allows the polymer to be dissolved and cast intofilms or coatings. It also allows active agents of poor water solubilitybut which are soluble in organic solvents, to be loaded into thepolymer.

In this description the term “equivalent weight” is used as meaning thenumber average molecular weight divided by the functionality of thecompound.

Polyethylene oxides contain the repeat unit (CH₂CH₂O) and areconveniently prepared by the stepwise addition of ethylene oxide to acompound containing a reactive hydrogen atom. Polyethylene glycols areprepared by the addition of ethylene oxide to ethylene glycol to producea difunctional polyethylene glycol structure HO(CH₂CH₂O)_(n)H wherein nis an integer of varying size depending on the molecular weight ofpolyethylene oxide. Polyethylene oxides used in the present inventionare generally linear polyethylene glycols i.e. diols having anequivalent weight of 1500 to 20,000, particularly 3000 to 10,000 andespecially 4000 to 8000. Molecular weights are usually in the region4000 to 35,000.

The difunctional compound is reactive with the difunctional isocyanate,and is typically a difunctional amine or diol. Diols in the range C₅ toC₂₀, preferably C₈ to C₁₅ are preferred. Thus, decane diol has beenfound to produce particularly good results. The diol may be a saturatedor unsaturated diol. Branched diols may be used but straight chain diolsare preferred. The two hydroxy groups are generally on terminal carbonatoms. Thus, preferred diols include 1,6-hexanediol, 1,10-decanediol,1,12-dodecanediol and 1,16-hexadecanediol.

The difunctional isocyanate is generally one of the conventionaldiisocyanates, such as dicyclohexylmethane-4,4-diisocyanate,diphenylmethane-4,4-diisocyanate, 1,6-hexamethylene diisocyanate etc.

The ratio of the components (a) to (b) to (c) (in terms of equivalentweights) is generally in the range 0.1-1.5 to 1 to 1.1-2.5, particularly0.2-0.9 to 1 to 1.2-1.9. A preferred range is 0.5-0.9 to 1 to 1.5-1.9 Ofcourse, the skilled man through reasonable experimentation woulddetermine the best ratio of ingredients to give the desired properties.The amount of component (c) is generally equal to the combined amountsof (a) and (b) to provide the correct stoichiometry.

Polymers produced at extreme ends of the ranges may not necessarily giveoptimal properties. For example, high amounts of (a) polyethylene oxidemay undesirably lead to the polymer being water-soluble. Small amountsmay reduce the percentage swelling. Generally, the ratio of (a)polyethylene oxide to (b) difunctional compound is preferably 0.1-1.5 toone, preferably 0.2-0.9 to one.

The polymers are generally produced by melting the previously driedpolyethylene glycol together with the difunctional compound (e.g. diol)at a temperature of around 85° C. A catalyst such as ferric chloride isincorporated. The molten mixture is dried under vacuum to remove excessmoisture and the diisocyanate added thereto. The reaction mixture isthen poured into billet moulds and cured for a specified time. Thus, thepolymer is initially formed as a moulded solid. However, the linearpolymers of the present invention are soluble in certain organicsolvents. This allows the polymer to be dissolved and the resultantsolution cast to form films. The solution may also be employed forcoating granules, tablets etc., in order to modify their releaseproperties. Alternatively, the solution can be poured into a non-solventso as to precipitate polymer/active microparticles.

Thus, the invention also provides controlled release compositionscomprising the linear polymer together with an active agent. The activeagent may be a pharmaceutically active agent for human or animal use. Itmay also be any other agent where sustained release properties (e.g.algicides, fertilisers etc.) are required. The pharmaceutical soliddosage forms include suppositories, pessaries for vaginal use, buccalinserts for oral administration etc. These dosage forms are generallyadministered to the patient, retained in place until delivery of activeagent has occurred and the spent polymer is then removed.

The linear polymer of the present invention may be swollen to a higherdegree than the conventional cross-linked polymer and is thus suitablefor the uptake of high molecular weight pharmaceutically active agents(up to and exceeding a molecular weight of 3000 e.g. up to 10,000, up to50,000, up to 100,000 or even up to 200,000 depending on swellability)and is thus particularly suitable for the uptake and delivery ofproteins and peptides. Generally, the molecular weight of the activeagent is in the range 200 to 20,00. A wide variety of water-solublepharmaceutically active substances such as those listed in EP0016652 maythus be incorporated. Furthermore, the linear polymers of the presentinvention may be loaded with pharmaceutically active agents which arepoorly water-soluble, provided that these can be dissolved in a commonsolvent with the polymer. The resultant solution can then be cast intoany desired solid forms. Pharmaceutically active agents of particularinterest include:

Proteins e.g. interferon alpha, beta and gamma, insulin, human growthhormone, leuprolide; Benzodiazepines e.g. midazolam; Anti-migraineagents e.g. triptophans, ergotamine and its derivatives; Anti-infectiveagents e.g. azoles, bacterial vaginosis, candida; and opthalmic agentse.g. latanoprost.

A detailed list of active agent includes H₂ receptor antagonist,antimuscaririe, prostaglandin analogue, proton pump inhibitor,aminosalycilate, corticosteroid, chelating agent, cardiac glycoside,phosphodiesterase inhibitor, thiazide, diuretic, carbonic anhydraseinhibitor, antihypertensive, anti-cancer, anti-depressant, calciumchannel blocker, analgesic, opioid antagonist, antiplatel,anticoagulant, fibrinolytic, statin, adrenoceptor agonist, beta blocker,antihistamine, respiratory stimulant, micolytic, expectorant,benzodiazepine, barbiturate, anxiolytic, antipsychotic, tricyclicantidepressant, 5HT₁ antagonist, opiate, 5HT, agonist, antiemetic,antiepileptic, dopaminergic, antibiotic, antifungal, anthelmintic,antiviral, antiprotozoal, antidiabetic, insulin, thyrotoxin, female sexhormone, male sex hormone, hormone, antioestrogen, hypothalamic,pituitary hormone, posterior pituitary hormone antagonist, antidiuretichormone antagonist, bisphosphonate, dopamine receptor stimulant,androgen, non-steroidal anti-inflammatory, immuno suppressant localanaesthetid, sedative, antipsioriatic, silver salt, topicalantibacterial, vaccine.

The invention also provides a method of manufacturing the linear polymerby reacting together components (a), (b) and (c).

Embodiments of the present invention will now be described by way ofexample only in Sections A and B.

Tests Carried Out on New Linear Polymer

All batches of linear polymer according to the invention were tested asfollows.

I. Appearance. The polymer should be free of air bubbles.

II. Percentage Swelling. Accurately weigh each of ten slices (to 3decimal places) and note the dry weight (mark each slice with an IDnumber). Swell the slices in 300 ml demineralised water at 25° C.±1° C.in a waterbath for 24 hours. Remove slices and blot dry with a papertowel. Reweigh each slice and determine the swelling factor as follows:$\begin{matrix}{\%\quad{Swelling}} \\({pph})\end{matrix} = {\frac{{{Swollen}\quad{weight}} - {{dry}\quad{weight}}}{{dry}\quad{weight}} \times \frac{100}{1}}$

III. Percent Water Soluble Extractables. (% WSE). Wash thoroughly anddry loss-on-drying vessels in an oven, overnight at 105° C., cool for 2hours in a desiccator and then weight. Record weight to 4 decimalplaces.

-   -   Accurately weigh out 10 slices and put into a 250 ml conical        flask. Add 150 ml demineralised water and swirl gently for 30        seconds. Decant the water and repeat. To the rinsed pessaries        add 50 ml demineralised water. Shake on a flat bottom shaker for        24 hours at room temperature.    -   Prepare 2 blanks (water only) and 2 samples (water+extract) each        time the determination is carried out. Calculate each individual        blank determination and the mean of these two values. This is to        be used to obtain the Corrected Total Weight. Decant the water        from the slices and pass ca 10 ml of the water (using a plastic        syringe) through a Millipore filter (1.2 um) into a previously        weighted LOD vessel and weigh again. Place in an oven at 105° C.        and evaporate sample to dryness (18 hours/overnight). Remove        from oven, cool for 2 hours in a dessicator and weigh.

Calculation—(All Weights in Grams)${{Total}\quad{Wt}\quad{of}\quad{Blank}} = {\begin{matrix}{{Wt}\quad{of}\quad{Residue}} \\{{In}\quad{LOD}\quad{Vessel}}\end{matrix} \times \frac{50}{\begin{matrix}{{Wt}\quad{of}\quad{water}\quad{added}} \\{{To}\quad{LOD}\quad{Vessel}}\end{matrix}}}$${{Total}\quad{Wt}\quad{of}\quad{Extract}} = {\begin{matrix}{{Wt}\quad{of}\quad{Extract}} \\{{In}\quad{LOD}\quad{Vessel}}\end{matrix} \times \frac{50}{\begin{matrix}{{Wt}\quad{of}\quad{sample}\quad{added}} \\{{To}\quad{LOD}\quad{Vessel}}\end{matrix}}}$ Corrected  Total  Wt = Wt  of  Extract − Wt  of  blank$\begin{matrix}{\%\quad( {w/w} )\quad{Water}} \\{{Soluble}\quad{Extractables}}\end{matrix} = {\frac{{Corrected}\quad{Wt}\quad{of}\quad{Extract}}{{Wt}\quad{of}\quad{Pessaries}\quad{Used}} \times 100}$

IV. Crystallinity. Cut a small portion from the slice and seal in a 50ul aluminium pan. Prepare a sealed empty pan of the same dimensions as areference. Place the pans in the sample and reference holdersrespectively and run the temperature programme. Calculate the onsettemperature and enthalpy using the Data Station. Crystallinity is equalto the ratio of the melt enthalpy of sample to melt enthalpy of 100%crystalline polyethylene oxide, enthalpies expressed in joules/g.${\%\quad{crystallinity}} = {\frac{{Enthalpy}\quad{of}\quad{sample}}{220.12} \times 100}$

V. Percentage Swelling 72 hours

VI. Percentage Swelling 144 hours

These percentage-swelling tests were carried out as the standardpercentage-swelling test but the total incubation time was increasedfrom 24 hours to either 72 or 144 hours.

Further selective tests included:

VII. Percentage Swelling Over Time

Where three slices of each polymer batch tested were immersed in waterand weighed at time intervals over a 24-hour period⁽¹⁰⁾. The percentageswelling was then calculated from these weights.

VIII. Stability Testing

Samples were tested for stability at 40° C. over a four-week period. Atthe specified time point intervals of one, two and four weeks thepercentage swelling (24 hours) was calculated and used as an indicationof polymer stability.

IX. Solubility in Different Solvents

Three polymer slices of each batch tested were placed into separatevials for each solvent used. For each batch, the different slices weretested twice using either whole or cut slices and to each vial around 10mL of solvent was added. The solvents used were acetone,dichloromethane, ethanol and methanol.

X. Water Solubility Testing

Ten slices of each batch tested were placed in a conical flask andaround 300 mL of demineralised water was added. The flasks were placedon a flat bottom shaker for seven days.

Section A

A1. Polymer Manufacture

Various stoichiometric ingredient ratios of PEG:DD:DMDI were used toproduce new polymers. Altering the ingredient ratio resulted in a changein the properties of the polymer. PEG is polyethylene glycol; DD isdecane-1,10-diol; and DMDI is dicyclohexyl methane-4,4-diisocyanate.TABLE 1 New Polymers Manufactured PEG:DD:DMDI Batch Numbers 1:1:2(comparison) FX02140, FX02143 0.7:1:1.7 FX02158 0.5:1:1.5 FX021480.25:1:1.25 FX02141, FX02144, FX02149, FX02161

(The ratio of the known cross-linked polymer FX02139 used for comparisonis PEG8000:hexanetriol:DMDI of 0.8:1.0:2.3)

PEG and DD were weighed into a round-bottomed flask balance and meltedovernight at a temperature of 85° C.

The required amount of ferric chloride (FeCl₃) plus an excess wasweighed into a tared 200 mL beaker with spatula. This was made up to 100g with molten PEG/DD from the previous step. This mixture ofPEG/DD/FeCl₃ was stirred vigorously and kept in the oven at 85° C., withfrequent stirring, until required.

The remaining molten PEG/DD was dried under vacuum at 95° C. for one anda half hours to remove excess moisture. The moisture content of thePEG/DD was tested using the volumetric Karl Fischer titration methodwith the specification for moisture being set at no more than 0.05%.

Next, 80 g of the PEG/DD/FeCl₃ mixture was weighed into a 2 L jug andthis ensured the correct weight of FeCl₃. The amount of PEG/DD required,taking into account the 80 g already present from the PEG/DD/FeCl₃mixture, was then added to the 2 L jug which was returned to the ovenwhilst setting up the equipment in the fume cupboard.

A mixer set at 427 rpm was used to agitate the contents of the 2 L jugfor 150 seconds, and the DMDI was added during the first 30 seconds.

This final mixture was then poured from the 2 L jug into billet moulds,placed in an oven at 95° C. and cured for a specified time, which rangedfrom 10 to 30 hours. After this time, the oven was turned off and thebillets left to cool to ambient.

The polymer was then demoulded, and the resultant polymer slabs sliced.

A2. Polymer Properties

(a) Characteristics of New Polymer

The characteristics of the new polymer batches manufactured aresummarised in Tables 2-5. TABLE 2 New polymer with a PEG:DD:DMDI ratioof 1:1:2 (Comparison) FX00206 FX01153 FX01167 FX02140 FX02143 (FK) (VJ)(VJ) (SS) (SS) Cure Time 20 hours 20 hours 20 hours 10 hours 20 hours 10minutes Appearance Normal Normal Normal looking looking but looking butdarker in darker in colour than colour than original original polymerpolymer Percentage  646%* 1334.14% 1918% 1110% 1320% Swelling RSD 1.82RSD RSD 0.8 RSD 4.37 2.58 % WSE 0.35%   2.03%**  7.54%**  1.11%** 1.24%***Polymer not sliced but cut into relatively thick slices**Filtrate too thick for filter paper

It was found that the new polymer with a PEG:DD:DMDI ratio of 1:1:2 lostits integrity during the water soluble extractable testing and onefurther test of water solubility was carried out on this ingredientratio to confirm this. These polymers were apparently water soluble toan extent and therefore unsuitable. TABLE 3 New polymer with aPEG:DD:DMDI ratio of 0.25:1:1.25 FX01156 FX02141 FX02144 FX02149 FX02161(VJ) (SS) (SS) (SS) (SS) Cure Time 20 hours 10 hours 10 hours 20 hours30 hours Appearance Golden Golden Normal Darker Darker yellow; yellow;looking colour than colour than undissolved undissolved but originaloriginal FeCl FeCl darker in polymer; polymer; present; present; colourundissolved some waxy waxy than FeCl undissolved original polymerpresent FeCl Percentage 427.41%   284%   287%   304%   304% Swelling RSD0.58 RSD 1.09 RSD RSD 0.62 RSD 0.35 0.77 % WSE  1.23%  0.16%  0.44% 0.24%  0.02% Crystallinity 43.63% 43.33% 44.50% 44.02% RSD 2.24 RSD RSD0.50 RSD 0.96 1.46

TABLE 4 New polymer with a PEG:DD:DMDI ratio of 0.5:1:1.5 FX01197 (VJ)FX02070 (LC) FX02148 (SS) Cure Time 20 hours 20 hours 10 hoursAppearance Darker colour than original polymer; air bubbles present;some undissolved FeCl present Percentage 422.4% 347% 492% Swelling RSD0.69 RSD 2.6 RSD 1.35 % WSE 0.1214% 0.1% Crystallinity 49.69% RSD 0.47

TABLE 5 New polymer with a PEG:DD:DMDI ratio of 0.7:1:1.7 FX02158 (SS)Cure Time 10 hours Appearance Darker in colour than original polymerPercentage Swelling 730% RSD 0.94 % WSE 0.73% Crystallinity 49.6% RSD2.06

(b) Extended Percentage Swelling TABLE 6 Results of Swelling at 24, 72and 114 Hours Percentage Percentage Percentage Percentage Increase BatchSwelling 24 Swelling 72 Swelling 144 from 24 to Number Hours Hours Hours144 Hours FX02141 284% 291% 293% 3% RSD 1.09 RSD 0.51 RSD 0.77 FX02144287% 299% 300% 5% RSD 0.77 RSD 0.33 RSD 0.51 FX02149 304% 311% 318% 5%RSD 0.62 RSD 0.99 RSD 1.00 FX02161 304% 308% 313% 3% RSD 0.35 RSD 0 . .. 43 RSD 0.66 FX02148 492% 504% 529% 8% RSD 1.35 RSD 1.04 RSD 2.20FX02158 730% 786% 827% 13% RSD 206 RSD 3.36 RSD 3.36 FX02139 308% 298%−3% (cross- RSD 0.59 RSD 0.76 linked)

(c) Percentage Swelling Over Time is given in FIGS. 1 and 2:

-   FIG. 1 shows Percentage Swelling Over Time of Two New Polymers    (FX02141 and FX02144) Compared With Original Polymer (FX02139); and-   FIG. 2 shows Percentage Swelling Over Time of Three New Polymers

(d) Stability of Linear Polymer TABLE 7 Stability Testing of FX02150(Purified FX02144) Time Percentage Swelling 0 (FX02144) 287% RSD 0.77 1week 370% RSD 4.57 2 week 374% RSD 5.10 4 week 379% RSD 2.81

(g) Solubility Testing of Linear Polymer TABLE 8 Solubility Testing ofNew Polymer in Four Different Solvents Batch Number AcetoneDichloromethane Ethanol Methanol FX02144 Polymer not Polymer dissolvedPolymer Polymer swollen swollen; slices resulting in a clear swollen,slices & broken up, white and in solution opaque and opaque & stillsmall pieces; intact; slices visible - settles forms appear smooth tobottom suspension on shaking but rapidly sediments FX02148 Polymer notPolymer dissolved Polymer Polymer swollen; slices resulting in a clearswollen, slices dissolved white & solution opaque and resulting in aclear breaking up intact; slices solution appear smooth FX02158 Polymernot Polymer dissolved Polymer Polymer swollen; slices resulting in aclear swollen; slices dissolved white; break solution slightly resultingin a up on vigorous opaque; clear solution shaking appear texturedFX02140 Polymer not Polymer dissolved Polymer Polymer swollen; slicesresulting in a clear swollen; slices dissolved white; break solutionclear and resulting in a up on vigorous textured clear solution shakinglooking

TABLE 9 Solubility Testing of New Polymer in Water Batch Number ResultsFX02144 Slices swollen and opaque. No signs of dissolving. Water clearFX02148 Slices swollen and opaque. No signs of dissolving. Water clearFX02158 Slices swollen and opaque. No signs of dissolving. Water clearFX02140 Slices lose their integrity and ultimately dissolve. WaterfrothyA3. Controlled Release CompositionsDissolution Testing

A dosage form when placed into a vessel containing liquid media willrelease drug in a defined manner dictated by the formulation. Thisprocess known as dissolution can be used as an in vitro marker of themechanism of release in the body. Sampling is carried out at regularintervals over a period of several hours and the amount of drug in thesamples is analysed by spectrophotometer or HPLC. The data are normallyrepresented as the release of labelled content against time.

(i) Pilocarpine

Potency

Ten units are swollen, macerated and quantitatively extracted into 500ml of mobile phase. Pilocarpine is then assayed by HPLC relative to areference standard. Detection is by UV spectrophotometer. The method iscapable of detecting pilocarpine and its main degradation products,pilocarpic acid, iso-pilocarpine and iso-pilocarpic acid. The method isbased upon the European Pharmacopeia method for pilocarpine.

Dissolution

Pilocarpine in vitro release from the units is performed by a USP paddlemethod at 50 rpm, 37° C. The pilocarpine released is assayed by HPLC asin the potency method.

Loading

The blank polymer slices are placed in purified water and agitated atabout 4° C. for approximately 16-20 hours; the water is then decanted.Water swollen polymer slices are placed in an ethanol:water solution andagitated at about 4° C. for approximately 6-8 hours. The slices are thendried. Pilocarpine is dissolved in water which is then added to the drypolymer slices. The slices and drug loading solution are agitated atapproximately 4° C. for approximately 16-20 hours to allow the uptake ofdrug. At the end of the dosing period the remaining drug solution isdecanted and the swollen polymer slices are dried for 18-28 hours.

Polymer batch FX02144 was purified (FX02150) and then loaded withpilocarpine (FX02151).

FIG. 3 shows normalised graph of percentage Pilocarpine released againsttime for linear polymer FX02151 compared with original polymer FX01234and FX01194

(ii) Loading with PGE₂ (Dinoprostone)

Potency

Ten units are swollen, macerated and quantitatively extracted into 500ml of mobile phase. Dinoprostone is then assayed by HPLC relative to areference standard. Detection is by UV spectrophotometer. The method iscapable of detecting Dinoprostone and its main degradation products,PGA2,8-iso PGE2 and 15 keto-PGE2. The method is based upon the EP methodfor dinoprostone.

Dissolution

Dinoprostone in vitro released from the units is performed by a USPpaddle method at 50 rpm, 37° C. The dinoprostone released is assayed byHPLC as in the potency method.

Purification and Loading

The blank polymer slices are placed in purified water and agitated atabout 4° C. for approximately 6-8 hours, then the water is decanted. Theswollen slices are again placed in purified water and agitated at about4° C. for approximately 16-20 hours; the water is then decanted. Waterswollen polymer slices are placed in an ethanol:water solution andagitated at about 4° C. for approximately 6-8 hours. A solution ofDinoprostone is made by dissolving the appropriate amount ofDinoprostone in ethanol. The resulting solution is added to water andethanol. This makes up the drug loading solution which is then added tothe swollen polymer slices to give a 25% w/w ethanol:water mix. Theslices and drug loading solution are agitated at, approximately 4° C.for approximately 16-20 hours to allow the uptake of drug. At the end ofthe dosing period the remaining drug solution is decanted and theswollen polymer slices are dried for 18-28 hours.

Prostaglandin E₂ was loaded by an analogous process into a batch ofcross-linked polymer (FX02139, loaded FX02159) and a batch of linearpolymer (FX02144, loaded FX02157), both with 0.6 mm thick slices. Themeasured potencies were 9.4 mg (FX02159, control) and 9.7 mg (FX02157)respectively.

FIG. 4 shows PGE₂ release profiles of cross-linked polymer and newlinear polymer.

A4. Manufacture of Films

In initial experimentation into film manufacture, six vials were set upcontaining one, two, three, four, five and eight slices of polymerrespectively. The polymer batch used was FX02141. To each vial around 10mL of dichloromethane was added. All vials were sonicated until thepolymer dissolved. The resultant solutions were poured onto a watchglass(20 cm diameter) and allowed to dry in a fume cupboard uncovered.

In further film development work, the amounts of polymer and solventwere weighed into a suitable glass container, which was then sealed andsonicated until the polymer dissolved. Some films were poured on awatchglass as before, whilst others were poured in a petri dish (8 cmdiameter). To control the drying of the films, some solutions pouredwere covered with a 1 L glass beaker.

Films were also manufactured using a doctor blade, with the solutionbeing poured onto a glass plate in a fume cupboard and spread along thelength of the plate. TABLE 10 Initial Film Manufacture Results Number ofSlices of FX02141 in 10 mL Dichloromethane (DCM) Notes on Resultant Film1 Lots of small air bubbles. 0.023 mm thick 2 Removed from glass tooquickly and film was self adhesive and formed a clump of sticky polymer3 Air bubbles present from shaking which leads to holes in film. Filmopaque in colour. 0.083 mm thick 4 Smooth, opaque film; some airbubbles. Around 8 cm in diameter. 0.112 mm thick 5 Good film that looksuniform on one side but half was partially stuck together due to beingremoved from watchglass before it was fully dry. 0.133 mm thick 8 Verystrong film; air bubbles a problem. Oval in shape - 7 cm by 5 cm. 0.354mm thick

The film made with five slices of polymer in solvent was swollen indemineralised water in a plastic petri dish. The swollen form of thefilm was found to be strong. The film was placed on a watchglass to dry.Once dried, the film regained its shape and strength. TABLE 11 FilmsManufactured Using Polymer Batch FX02141 Dissolved in DichloromethaneWeight % w/w Weight DCM Polymer in Vial FX02141 (g) added (g) DCMDetails 1 0.8911 12.763 6.98 Loaded with cresol red. 2 0.9478 13.8066.87 Loaded with bromophenol blue 3 0.7897 14.797 5.34 Poured ontowatchglass with another watchglass placed on top; film not uniform 40.9238 10.661 8.67 Poured onto watchglass; film used for swelling overtime test 5 0.9572 15.936 6.01 Poured onto watchglass, covered with a 1litre beaker; film uniform 6 0.8679 13.899 6.24 Poured into a glasspetrie dish, covered with beaker; uniform film; film used forcrystallinity testing; film brittle 7 0.9751 15.286 6.38 Poured in aglass petrie dish, covered with beaker; film brittle 8 1.0680 11.1939.54 Made into a 53.20% w/w solution of ethanol in DCM/polymer mixture;didn't go into a film 9 1.0618 13.335 7.96 Loaded with bromophenol blue;film swollen 10 0.8490 11.557 7.35 Made into a 34.73% w/w solution ofacetonitrile in DCM/polymer mixture; film brittle - opaque looking 110.6528 10.029 6.51 Made into a 45.00% w/w solution of methanol inDCM/polymer mixture 12 0.9013 6.541 13.78 Made into a 108% w/w solutionof acetone in DCM/polymer mixture, poured onto watchglass and coveredwith beaker; film not uniform

Portions of films made from Vials 1 and 2 were cut and placed into vialsof demineralised water to determine whether the film could release theloaded dye. TABLE 12 Films Manufactured Using Polymer Batch FX02158 inDifferent Solvents % w/w Weight Polymer FX02158 Weight Solvent in Vial(g) Added (g) Solvent Details A 0.7677 10.0211 g 7.66 Non-uniform: onelarge methanol clearer patch visible; feels smooth; opaque film;slightly textured looking C 0.7755 15.9041 g 4.88 Uniform in appearance;dichloromethane opaque film covered in small clear spots all over; feelsrough; not brittle E 0.7631  9.6095 g 5.23 Uniform film; smooth todichloromethane touch; very brittle and and 4.9686 g breaks on touching;methanol opaque film covered in clear spots which are smaller and morespread out than vial c

The polymer in vials C and E began dissolving immediately, whereas vialA was slower. The solutions from these vials were poured into separateglass petri dishes in a fume cupboard and each covered with a one-litrebeaker. They were left until dry. It was noticed that the solution fromvial c dried quicker than that of vials a and e. TABLE 13 FilmsManufactured to Compare Drying Techniques Weight Polymer Weight DCM %w/w polymer in Duran (g) (g) DCM 1 1.9542 37.2 5.25 FX02158 2 1.980635.6 5.56 FX02158 3 1.8595 40.0 4.65 FX02144 4 1.8508 37.0 5.00 FX02144

The solutions from all four durans were poured separately into glasspetri dishes in a fume cupboard.

Durans 1 and 3 were covered with a one-litre glass beaker, and durans 2and 4 were left uncovered.

Films from durans 1 and 3 feel rough to touch, whereas films from durans2 and 4 are smooth. Film from duran 2 has a rougher patch at one side.

All films manufactured from durans 1-4 were of comparable strength andnone were brittle.

Two films were manufactured using the doctor blade. Both polymers usedwere dissolved in DCM (about 5% w/w) to make the solution, and bothsolutions were poured onto the same glass dish under the sameconditions.

The film manufactured with polymer FX02144 was brittle and fell apart onstorage whereas the film made with FX02158 (which was loaded withbromophenol blue for a demonstration) remained intact.

To access the release of a drug from a polymer film, the percentageswelling over time was calculated. This was graphically represented,using the percentage swelling over time of the polymer slice of samebatch used in film manufacture as a reference. The results are shown inFIG. 5.

The average weight of a film portion used was 0.0272 g; and the averageweight of a polymer slice (FX02141) was 0.1381 g.

A5. Discussion

a. Appearance

During appearance testing, it was observed that new linear polymerbillets were slightly darker in colour when compared to knowncross-linked polymer billets. This was accounted for by comparing theFeCl₃ content in both. It was calculated that known cross-linked polymercontained 0.01% w/w FeCl₃ in PEG whereas linear polymer had 0.0266% w/wFeCl₃ in PEG.

b. Cure Time

Previous linear polymers were manufactured with a 20 hour cure time,however batches FX02140 and FX02141 were manufactured with a 10 hourcure time.

By comparison of two batches with the same ingredient ratio butdifferent cure times [FX02140 (10 hour cure time) and FX02143 (20 hourcure time)], it was seen that a cure time of 10 hours produced morepromising results with a lower RSD for percentage swelling test and alower percent water soluble extractables. As a result, a 10 hour curetime was then used for batches FX02144, FX02148 and FX02158.

However, the effect of cure time was further investigated using batchesFX02141, FX02149 and FX02161 with cure time of 10, 20 and 30 hoursrespectively. By comparison of results from these three batches, it wasfound that there was no correlation in crystallinity; % WSE decreased asthe cure time increased and the percentage swelling for FX02144 is about20% less than the swellings of FX02149 and FX02161 which are identical.The RSD for percentage swelling decreased are cure time increased.

c. Ingredient Ratio

Polymer manufactured with a PEG:DD:DMDI ratio of 0.25:1:1.25 was shownto have the same characteristics as the cross-linked polymer, with allresults within the known cross-linked polymer specifications.

The linear polymer according to the invention meets these specificationsand the results are reproducible. Furthermore, the linear polymer issoluble in certain solvents whereas the known cross-linked polymer isinsoluble.

The known cross-linked polymer, with a percentage swelling of around300%, cannot be loaded with drugs of high molecular weight, such aspeptides and proteins.

In comparison, a linear polymer of the present invention, FX02158(PEG:DD:DMDI 0.7:1:1.7), was shown to have a percentage swelling of 730%and insoluble in water.

d. Swelling Profile

As the ratio of PEG:DD increased, the percentage swelling at 24 hoursalso increases. The accepted percentage swelling test for the knowncross-linked polymers in 24 hours. This was extended to 72 and 144 hoursfor the polymer according to the invention to ascertain the timerequired for the polymer slice to reach maximum swelling.

With higher rations of PEG:DD, it was found that the percentage swellingincreased by a larger difference between 24 and 144 hours when comparedto polymers with a low PEG:DD ratio. There was a 3% increase inpercentage swelling of FX02141 (PEG:DD 0.25:1) from 24 to 144 hourscompared to a 13% increase in FX02158 (PEG:DD:0.7:1).

Polymers with higher PEG:DD ratios have not reach their maximumpercentage swelling by 24 hours. This is confirmed by percentageswellings over time curves (FIG. 2). Polymer slices with a PEG:DD ratioof 0.25:1 reach their maximum swelling by around 5 hours when the curveplateaus, however, polymer slices with a higher PEG:DD ratio of 0.7:1 itwas seen that the percentage swelling was increasing at 144 hours withthe gradient of the curve at this point being positive.

e. Stability

Stability testing at 40° C. was carried out on FX02150 (purifiedFX02144) over a period of 4 weeks. The results have shown that thepercentage swellings increased with time and this is comparable toresults of cross-linked polymers at 4° C.

f. Drug Release

Polymer batch FX02144 (PEG:DD:DMDI 0.25:1:1.25) was loaded withpilocarpine and PGE₂. This polymer has similar characteristics tocross-linked polymer and therefore, release profiles of both drugs fromthe two different polymers could be compared.

The release characteristics of pilocarpine were shown to be comparablebetween linear and cross-linked polymer. This was confirmed bycomparison of percentage swelling over time of the linear batch withcross-linked polymer (FIG. 1) where the rate of swelling was the samefor both.

However, PGE₂ release was found to be different. The linear polymerreleased the drug slower than the cross-linked polymer.

g. Solubility Testing

Four different polymers, with different ingredient ratios, weremanufactured and none of these polymers were soluble in ethanol oracetone.

FX02144 was insoluble in methanol, whereas other batches tested weresoluble in this solvent.

All batches tested were soluble in dichloromethane.

h. Film Preparation

From initial experimentation a promising combination of polymer andsolvent was found to be 4-5 slices (approx equivalent to 0.7 g polymer)in 10 mL DCM. This was scaled up to 13 slices in 30 mL DCM and the filmmanufacture was shown to be reproducible with similar films achievedusing this combination.

A manufactured film was swollen in demineralised water and the swollenform was found to be strong and stretchy. This swollen film was thenremoved from the water and allowed to dry. Once dried the film regainedits shape and strength.

On further film development, the film was tested to determine whether itcould release a loaded dye. Portions of films loaded with dye weresubmerged in water, and the water colour changed over time showing thatthe film had the ability to release a loaded substance.

It was discovered that a film manufactured by dissolving the polymer indifferent solvents had an effect on the total drying time of the film,the uniformity, texture and strength of the final film. In addition, thetechnique used to dry the films had an effect on its final appearance interms of uniformity and texture.

The percentage swelling over time of a polymer film produced wascalculated, and compared to the percentage swelling over time of thepolymer slices used to make the film. As expected, the portions of filmreached their maximum percentage swelling much quicker than the polymerslice because the thickness and average weight of the film portions weremuch less than the polymer slices. This can be used as an indication ofrelease rate of a drug from a polymer film.

Section B

B1 Polymer Manufacture

Various type of polyethylene glycols, diols and diisocyanates, andvarious stoichiometric ratios of these compounds were used to furtherdemonstrate their effects on the properties of the new polymer. PEG4000,PEG8000, PEG12000 and PEG35000 are polyethylene glycols having molecularweight of 4000, 8000, 12000 and 35000, respectively; HD is1,6-hexanediol, DD is 1,10-decanediol, DDD is 1,12-dodecanediol and HDDis 1,16-hexadecanediol; DMDI is dicyclohexylmethane-4,4-diisocyanate andHMDI is 1,6-hexamethylene diisocyanate.

Polymers, except batch numbers BP03007, BP03014 and BP03015, wereproduced with the same polymerisation method as in Section A. The onlydifference was that the melted PEG and diol mixture was mixed for 30mins. in a rotavapor, before 100 g was taken out to make a catalystmixture to produce a more homogenous mixture.

For polymerisation of PEG35000 (batch numbers BP03007 and BP03014) thepolymerisation reactor was changed to a stirring tank reactor (700 ml)and the polymerisation temperature was increased to 140° C. to reducethe melt viscosity of the PEG. PEG was dried overnight in a rotavaporusing vacuum and 50° C. temperature. PEG, diol and ferric chloride werefed to a stirring tank glass reactor. The mixture was melted for 2 hoursunder nitrogen using a 140° C. oil bath. Mixing was turned on for 30 minbefore diisocyanate was fed to the reactor and then mixed for 5 min.Polymer was poured to the preheated mould (130° C.) and kept for 10hours in an oven at 95° C. After this time, the oven was turned off andthe polymer billets were left to cool to room temperature. The polymerbillets were then demoulded and sliced.

A two-step polymerisation method was also used to produce morecontrolled polymer structure (batch number BP03015). PEG was driedovernight using vacuum and 50° C. in a rotavapor. Diisocyanate was firstfed to the stirring tank reactor. Then about 40 g PEG with ferricchloride on the top of it was fed to the reactor. The reactor was heatedto 95° C. and PEG was fed to the reactor during 3 hours by using about20 g portions at the each time. Mixing (30 rpm) was turned on when thereactor temperature reached 95° C. Then the diol was fed to the reactorand mixing increased to 60 rpm and mixed for 5 min. Polymer was pouredinto the preheated mould (95° C.) and kept for 10 hours in an oven at95° C. After this time, the oven was turned off and the polymer billetswere left to cool to room temperature. The polymer billets were thendemoulded and sliced.

B2. Polymer Properties

The effects of type and ratios of polyethylene glycols, diols anddiisocyanates on the properties of polymers can be seen in Tables 14-18.TABLE 14 Molar ratios between PEG 8000 and 1,10-decanediol was changed.Batch Number 03032 03030 03031 03033 PEG 8 000 0.9 0.7 0.7 0.1 (MolarRatio) DD 1 1 1 1 (Molar Ratio) DMDI 1.9 1.7 1.7 1.1 (Molar Ratio) CureTime 10 10 10 10 Percentage 1048 612 750 178 Swelling (%) WSE (%) 2.31.0 1.4 2.3 Tm (° C.) 62.4 61.4 62.4 54.9 Crystallinity 48.6 52.7 49.333.1 (%) Soluble in yes yes yes yes DCM Soluble in no no no yes THFDD is 1,10-decanediolDMDI is dicyclohexylmethane-4,4-diisocyanateWSE is water soluble extractable

TABLE 15 The length of PEG was changed. Batch Number Bp03001 03031BP03005 BP03007 BP03014 PEG (MW) 4 000 8 000 12 000 35 000 35 000 PEG   0.7    0.7    0.7    0.7    0.1 (Molar Ratio) DD    1    1    1    1   1 (Molar Ratio) DMDI    1.7    1.7    1.7    1.7    1.1 (Molar Ratio)Cure time   10   10    10    10    10 Percentage   395   750   993 Lost  742 Swelling (%) Intergrity WSE (%)    1.3    1.4 N.D. WS CH Tm (° C.)  53.8   62    64.0    65.7    65.3 Crystallinity   36.3   49.3    46.5   64.7    46.4 (%) Soluble in yes yes yes yes yes DCM Soluble in yes nono no no THFMW is molecular weightDD is 1,10-decanediolDMDI is dicyclohexylmethane-4,4-diisocyanateWS water solubleCH changes in shapes

TABLE 16 The length of diol and the amount of diol was changed. BatchNumber 03035 03031 Bp03002/1 03036 03034 BP03006 Diol HD DD DDD DDD DDDHDD PEG 8 000 0.7 0.7 1.5 0.9 0.7 0.7 (molar ratio) Diol 1 1 1 1 1 1(molar ratio) DMDI 1.7 1.7 2.5 1.9 1.7 1.7 (molar ratio) Cure Time 10 1010 10 10 10 Percentage Swelling (%) 899 751 1679 602 640 470 WSE (%)0.92 1.4 5.7 0.7 0.89 N.D. Tm (° C.) 61.8 62 61.1 60 60.6 60.1Crystallinity 52.8 49.3 48.7 43.1 38.2 45.8 (%) Soluble in yes yes yesyes yes yes DCM Soluble in no no no no no no THFHD is 1,6-hexanediolDD is 1,10-decanediolDDD is 1,12-dodecanediolHDD is 1,16-hexadecanediolDMDI is dicyclohexylmethane-4,4-diisocyanate

TABLE 17 The effect of diisocyanate. Batch Number 03031 BP03003Diisocyanate DMDI HMDI PEG 8 000 0.7 0.7 (molar ratio) DD 1 1 (molarratio) DMDI 1.7 1.7 (molar ratio) Cure Time 10 10 Percentage 751 1070Swelling (%) WSE (%) 1.4 N.D. Tm (° C.) 62 63.4 Crystallinity 49.3 52.2(%) Soluble in yes yes DCM Soluble in no no THFDMDI is dicyclohexylmethane-4,4-diisocyanateHMDI is 1,6-hexamethylene diisocyanate

TABLE 18 Two-step Polymerisation method Batch number BP03016 PEG 8 0000.7 (molar ratio) DD 1 (molar ratio) DMDI 1.7 (molar ratio) Cure Time 10Percentage 1750 Swelling (%) WSE (%) N.D. Tm (° C.) 61.2 Crystallinity52.4 (%) Soluble in yes DCM Soluble in no THFDD is 1,10-decanediolDMDI is dicyclohexylmethane-4,4-diisocyanateB3 Controlled Release CompositionsLinear Polymer Characterisation & Drug Loading Examples

Batches of linear polymer (03030, 03032 and 03033), together withcross-linked polymer batch 03003 (polymer ratio PEG8000:hexanetriol:DMDI of 1.0:1.2:2.8) for comparison were sliced toproduce polymer slices of dimension 10 mm×30 mm×11.0 mm. The polymerslices were purified at 25° C. using three washes in purified waterand/or purified water/ethanol. Next, all slices were dried under vacuum.

Five drugs namely clindamycin phosphate, oxytocin, terbutaline sulphate,misoprostol and progesterone were loaded into the various polymers.These drugs were chosen as they covered various aspects such as highlywater soluble, poorly water soluble, peptides, steroids and lowermolecular weight molecules.

The drugs were loaded into the polymer by dissolving each drug candidateinto a suitable solution, immersing the polymer slices for anappropriate time then removing from the solution and drying. Table 19details the loading parameter and conditions. TABLE 19 Loadingparameters for various drug candidates Drug CLI OXY TBS MIS PRO GeneralBatch no. A03003 (CLP) CL 03009 OX 03001 FX 02248 MS 03025 PG 03002A03030 (LP) CL 03017 OX 03002 TB 03001 MS 03030 — A03032 (LP) CL 03020OX 03003 TB 03002 — — A03033 (LP) — — — MS 03033 PG 03003 Drugcontent/unit 70 mg 1 mg 10 mg 200 μg 10 mg Drug solubility Very solubleVery soluble Soluble Insoluble Insoluble (in water) (500 mg/ml) (250mg/ml) (3 mg/ml) (<0.4 mg/ml) No. of pessary (n) 18-23 18-23 18-23 18-2318-23 Loading Loading solution 4.76% w/w PBS solution Purified water 25%w/w 75% w/w NaCl solution (pH 7.4) EtOH EtOH solution solution Loadingtemperature 25° C. 25° C. 25° C. 4° C. 25° C. Incubation Incubationtemperature 25° C. 25° C. 25° C. 4° C. 25° C. Incubation duration 16-24hours 16-24 hours 16-24 hours 16-24 hours 16-24 hours Drying Dryingmethod Vacuum oven Vacuum oven Vacuum oven Vacuum oven Rotavapor Dryingtemperature Room Room Room Room Room temperature temperature temperaturetemperature temperature Drying duration ≧72 hours ≧24 hours ≧24 hours≧24 hours ≧24 hours (as required) (as required) (as required) (asrequired) (as required)Abbreviations:CLI—Clindamycin phosphate;OXY—Oxytocin;TBS—Terbutaline sulphate;MIS—Misoporstol;PRO—Progesterone;NaCl—Sodium chloride;PBS—Phosphate buffered saline;EtOH—Ethanol

The drug loaded polymer were analysed for in vitro drug releasefollowing USP Method XXIII, Apparatus 2 at 37° C., with 50 rpm paddlespeed. Drug release was analysed by ultraviolet spectroscopy or highpressure liquid chromatography (HPLC) as appropriate. Variousdissolution parameters or settings are summarised in Table 20. TABLE 20Dissolution parameters and settings Drug CLI OXY TBS MIS PRO Dose per 70  1  10 0.2  10 unit (mg) Dissolution 900 100 250 250 ml 900 volume,V (ml) Dissolution Water Phosphate Water Water Water media buffersolution (pH 7.4) Wavelength, 210 562 276 280 (after 249 λ (nm)derivitisation)Abbreviations:CLI—Clindamycin phosphate;OXY—Oxytocin;TBS—Terbutaline sulphate;MIS—Misoporstol;PRO—Progesterone;NA—Not available

FIG. 6 to 10 show the mean dissolution profiles of each drug candidatefrom the various polymers.

The effect of drug type on mean dissolution profile of linear polymerbatch A03030 is shown in FIG. 11.

Rate of drug release k values of each dissolution profile was determinedby calculating the slope of graph % drug release versus square roottime. All the linear relationship between % drug release and square roottime has R² correlation value >0.95%. Rate of drug release k from thedissolution profiles of each drug candidate from various pessaries areshown in Table 21. TABLE 21 Rate of drug release (k minutes^(−1/2)) ofdrug candidates from cross- linked and linear polymer pessaries Rate ofdrug release, k (minute^(−0.5)) Polymer type Water A03003 (CLP) A03033(LP) A03030 (LP) A03032 (LP) solubility Molecular % Swelling (in water)(mg/ml) weight Drug 295.4 230.0 678.9 1202.8 500 505 CLI 10.701 -ND-12.765 12.380 Very 1007 OXY 6.749 -ND- 7.875 7.85 soluble 250 274 TBS13.628 -ND- 13.262 11.954  3 383 MIS 4.507 2.213 4.378 -ND-   <0.4 315PRO 2.414 1.256 -ND- -ND-Abbreviations:CLI—Clindamycin phosphate;OXY—Oxytocin;TBS—Terbutaline sulphate;MIS—Misoporstol;PRO—Progesterone;CLP—Cross-linked polymer;LP—Linear polymer;ND—No data

1. A water-swellable linear polymer obtainable by reacting together (a)a polyethylene oxide; (b) a difunctional compound, and (c) adifunctional isocyanate.
 2. A polymer according to claim 1 wherein thepolyethylene oxide has a number average molecular weight of 4000 to35,000.
 3. A polymer according to claim 1 wherein the polyethylene oxidehas a number average molecular weight of 8000 to 12,000.
 4. A polymeraccording to claim 1 wherein the difunctional compound is a diamine ordiol.
 5. A polymer according to claim 4 wherein the diol is a C₅ to C₂₀diol.
 6. A polymer according to claim 5 wherein the diol is a1,10-decanediol.
 7. A polymer according to claim 5 wherein the diol is1,6-hexanediol, 1,12-dodecanediol or 1,16-hexadecanediol.
 8. A polymeraccording to claim 1 wherein the ratio of components (a) to (b) to (c)in terms of equivalent weights is in the range 0.1-1.5 to 1 to 1.1-2.5.9. A polymer according to claim 8 wherein the ratio is 0.2-0.9 to 1 to1.2-1.9
 10. A polymer according to claim 9 wherein the ratio is 0.5-0.9to 1 to 1.5-1.9
 11. A polymer according to claim 1 which is swellable inwater up to 500%.
 12. A polymer according to claim 1 which is swellablein water up to 1700%.
 13. A polymer according to claim 1 which issoluble in dichloromethane.
 14. A method of making a polymer accordingto claim 1 which comprises reacting together components (a), (b) and(c).
 15. A controlled release composition which comprises a polymer ofclaim 1 together with an active agent.
 16. A composition according toclaim 15 wherein the molecular weight of the active agent is in therange 200 to 20,000.
 17. A composition according to claim 15 wherein theactive agent is a prostaglandin.
 18. A composition according to claim 15wherein the active agent is terbutaline sulphate, clindamycin sulphate,oxytocin, misoprostol or progesterone.
 19. A composition wherein theactive agent is an H₂ receptor antagonist, antimuscaririe, prostaglandinanalogue, proton pump inhibitor, aminosalycilate, corticosteroid,chelating agent, cardiac glycoside, phosphodiesterase inhibitor,thiazide, diuretic, carbonic anhydrase inhibitor, antihypertensive,anti-cancer, anti-depressant, calcium channel blocker, analgesic, opioidantagonist, antiplatel, anticoagulant, fibrinolytic, statin,adrenoceptor agonist, beta blocker, antihistamine, respiratorystimulant, micolytic, expectorant, benzodiazepine, barbiturate,anxiolytic, antipsychotic, tricyclic antidepressant, 5HT, antagonist,opiate, 5HT, agonist, antiemetic, antiepileptic, dopaminergic,antibiotic, antifungal, anthelmintic, antiviral, antiprotozoal,antidiabetic, insulin, thyrotoxin, female sex hormone, male sex hormone,antioestrogen, hypothalamic, pituitary hormone, posterior pituitaryhormone antagonist, antidiuretic hormone antagonist, bisphosphonate,dopamine receptor stimulant, androgen, non-steroidal anti-inflammatory,immuno suppressant local anaesthetic, sedative, antipsioriatic, silversalt, topical antibacterial, vaccine.
 20. A composition according claim15 in the form of a suppository, pessary, buccal insert or film.